The insulin-like growth factors (IGFs) play essential roles in pre-natal and post-natal growth and development. In rodents, IGF-I is widely expressed and homozygous null mutants result in fetal growth retardation, peri-natal mortality and growth retardation, and infertility in surviving offspring. There remains, however, a fundamental question regarding the role of circulating (endocrine form) IGF-I in growth and development versus the local tissue production of IGF-I (autocrine/paracrine form). To answer this question, we have used the homologous recombination technique that utilizes the Cre recombinase/loxP system. The loxP sequences were introduced into the mouse genome flanking exon 4 of the IGF-I gene and these animals were mated with mice expressing Cre cDNA driven by the EIIa promoter. In these mice, recombination occurs at the pre- implantation stages. The resultant mice demonstrate generalized deletion of exon 4 and varying degrees of reduction in IGF-I mRNA. In this model, even in the total absence of IGF-I gene expression, more animals survived than seen with the two previous reports of homologous recombination/null mutations of the IGF-I gene. These animals showed severe post-natal growth retardation, greater than 50 percent of wild-type littermates, and this reduction in growth was not reversed by recombinant human growth hormone (GH) given twice daily. Thus it seems that GH is incapable of stimulating longitudinal growth during the peri-pubertal period in the absence of IGF-I. The second model utilized the loxP-flanked IGF-I gene mice mated with mice expressing Cre exclusively in the liver; the Cre cDNA being driven by the albumin promoter. Exon 4 of the IGF-I gene was totally deleted as seen on Southern blot analysis, and IGF-I mRNA was no greater than 2 percent of wild-type littermates, as shown by Solution hybridization/RNase protection assay. Despite the reduction in circulating IGF-I levels, these animals showed normal growth and development over the 6 to 8 weeks of post-natal development. IGF-I mRNA levels in extra-hepatic tissues, including kidney and fat, were not increased in the homozygous IGF-I-depleted animals. These findings suggest that while the liver is a major source of circulating IGF-I, normal post-natal growth and development can occur in the absence of hepatic IGF-I production. Studies are on-going to test the role of paracrine/autocrine IGF-I in growth and development.